Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 ORAL PRESENTATION Open Access A bispecific chimeric antigen receptor molecule enhances T cell activation through dual immunological synapse formation and offsets antigen escape in glioblastoma Meenakshi Hegde1*, Zakaria Grada1, Antonella Pignata1, Amanda Wakefield1, Kristen Fousek1, Kevin Bielamowicz1, Kevin Chow1, Vita Brawley1, Tiara Byrd1, Stephen Gottschalk1, Malini Mukherjee1, Winfried S Wels2, Matthew Baker1, Giapietro Dotti1, Jordan Orange1, Nabil Ahmed1 From 30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015) National Harbor, MD, USA 4-8 November 2015 Background Antigen escape tumor cell variants prevail in tumors recurring after treatment with chimeric antigen receptor (CAR) T cells with a single specificity Recurrent tumors preserve alternative non-targeted tumor associated antigens Hypothesis A bispecific CAR will mitigate antigen escape enhancing the antitumor activity of T cells Methods and results HER2 and IL13Ra2 are currently targeted in Phase I glioblastoma (GBM) trials using CAR T cells We created a bispecific CAR molecule with a HER2-specific scFv joined in tandem to an IL13Ra2-binding moiety in the CAR exodomain (Tandem CAR) and a CD28.ζ signaling endodomain We used computational modeling to interrogate this design GBM patients’ Tandem CAR T cells showed distinct binding to soluble HER2 and IL13Ra2 and killed primary autologous GBM cells Three-dimensional reconstitution and quantification of confocal images of the Tandem CAR T cell/tumor interface revealed enhanced bifunctional immunological synapses compared to conventional CARs Further, Tandem CAR T cells exhibited significantly enhanced inexhaustible activation dynamics when compared to conventional HER2 or IL13Ra2 CAR T cells and better controlled established GBM in an orthotopic murine model by offsetting both HER2 and IL13Ra2 escape Conclusion Tandem chimeric antigen receptors enhance T cell activation and mitigate antigen escape through bifunctional immunological synapse formation in GBM Authors’ details Baylor College of Medicine, Houston, TX, USA 2Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany Published: November 2015 doi:10.1186/2051-1426-3-S2-O3 Cite this article as: Hegde et al.: A bispecific chimeric antigen receptor molecule enhances T cell activation through dual immunological synapse formation and offsets antigen escape in glioblastoma Journal for ImmunoTherapy of Cancer 2015 3(Suppl 2):O3 Baylor College of Medicine, Houston, TX, USA Full list of author information is available at the end of the article © 2015 Hegde et al This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Figure Page of Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Page of Figure Figure Figure Figure Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Figure Figure Page of ...Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Figure Page of Hegde et al Journal for ImmunoTherapy of Cancer 2015,... 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Page of Figure Figure Figure Figure Hegde et al Journal for ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3... ImmunoTherapy of Cancer 2015, 3(Suppl 2):O3 http://www.immunotherapyofcancer.org/content/3/S2/O3 Figure Figure Page of